PILOT/DEMONSTRATION PROJECTS The primary purpose of the CREATE RDCRC pilot/demonstration research program is to promote biomarker discovery and validation for ALS and related disorders through a small research grant program that funds studies of potential biomarkers during their early stages of development. Priority is given to projects with the most promising clinical research potential. The activities of the CREATE Consortium - longitudinal evaluation of patients with familial and sporadic disease, collection of deep phenotypic data, and the establishment of a repository of biological samples (blood, urine, cerebrospinal fluid) that has been annotated clinically in a detailed manner - are all expected to enhance and facilitate biomarker discovery through the pilot/ demonstration research program. The first pilot/demonstration project will focus on early development of a cerebrospinal fluid biomarker for ALS. Potential projects in subsequent years include development of a urinary biomarker of disease progression and a neuroimaging marker of the imbalance between cortical inhibition and excitability. The CREATE RDCRC will utilize a request for applications on an annual basis, to solicit applications and to select the most promising project for funding.